Selegiline, or (−)-N,α-dimethyl-N-2-propynyl-phenethylamine, is known to be useful in the treatment of Parkinson's disease. The mechanism of action of selegiline has not been fully elucidated. Selegiline, however, is a potent irreversible inhibitor of monoamine oxidase, with a greater affinity for the type B form of the enzyme. Monoamine oxidase is known to play an important role in the breakdown of biological amines, such as dopamine, noradrenaline and 5-hydroxytryptamine (serotonin) in the brain. It is thought that the inhibition of monoamine oxidase type B (MAO-B) may lead to enhancement of the effects of dopamine and phenethylamine in the brain of patients with Parkinson's disease, thus leading to improved control of movement. See for example, Gaal and Hermez, Inhibitors of Monoamine Oxidase B, Pharmacology and Clinical Use in Neurodegenerative Disorders, (edited by I. Szelenyi, Birkhauser Verlag, Basel, Switzerland), Chapter 4 (1993) (hereinafter referred to as Szelenyi).
Selegiline is currently administered orally in the form of conventional tablet design and to be swallowed whole. Alternatively, selegiline is also administered in a measure amount of syrup for rapid swallowing. Accordingly, selegiline administered this way is absorbed from the gastrointestinal tract, that is, the stomach, small intestine and the proximal large intestine (colon), into the hepatic portal system and is presented to the liver before reaching systemic circulation.
One problem associated with the administration of conventional tablet forms of selegiline is that the liver is known to be the principal site for conversion of active selegiline into metabolites, some of which are undesirable. Consequently, this first pass of absorbed selegiline through the liver results in extensive metabolism of the drug, and a significant proportion of the absorbed dose of intact selegiline never reach systemic circulation or, therefore, the brain. This phenomenon is generally known as the “first pass effect”, and results in a decrease in the bioavailability of selegiline administered in the conventional manner. See, for example, Heinonen et al., Clinical Pharmacology & Therapeutics, Vol. 56, No. 6 (1994), pp. 742-749.
Another problem with conventional selegiline is its undesired metabolites. It is known that selegiline is metabolized to produce N-desmethylselegiline, methamphetamine and amophetamine according to the following metabolic pathway:

Although it has been suggested that N-desmethylselegiline may contribute to the desired inhibition of monoamine oxidases (see, for example, Heinonen et al. in Chapter 10 of Szelenyi), methamphetamine and amphetamine exhibit no useful effect in Parkinson's disease. Indeed, since methamphetamine and amphetamine are both stimulants of the central nervous system and of the heart, their presence produces undesirable side-effects such as insomnia and cardiac arrhythmias. In order to minimize the central nervous system stimulant effect, currently available dosage forms of selegiline must be administered by no later than mid-day so that the unwanted stimulant effect will subside at the end of the day. Clearly, this situation is far from satisfactory.
Yet another problem associated with conventional selegiline administration is that which is associated with its co-administration with levodopa. Co-administration of selegiline with levodopa has even been associated with fatalities, and unadjusted (unreduced) amounts of levodopa can cause dyskenesias (defects in the ability to perform voluntary movement).
Yet another undesired side-effect of conventional selegiline administration is orthostatic hypotension and syncope is some patients, which has been linked to non-selective MAO inhibition. Conventional selegiline can also cause undesirable and capricious side effects due to sudden changes in plasma concentration of selegiline itself and/or its known metabolites. The presence or absence of food in the digestive tract may also contribute to the unpredictability.
One analogue of selegiline, para-fluoroselegiline, is also a monoamine oxidase B inhibitor and exhibits very similar pharmacological activity to that of selegiline. Many other compounds, some of which are not chemically related to selegiline, also have monoamine oxidase B-inhibiting properties. A number of these have also demonstrated utility for treatment of Parkinson's disease, treatment of depression, and/or treatment or prophylaxis of Alzheimer's disease. Among such MAO-B inhibitors are: lazabemide (N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride); rasagiline (2,3-dihydro-N-2-propynyl-1H-inden-1-amine); 2-BUMP (N-(2-butyl)-N-methylpropargylamine); M-2-PP (N-methyl-N-(2-pentyl)-propargylamine); MDL-72145 (beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine); and mofegiline (E)-4-fluoro-β-(fluoromethylene) benzene butanamine hydrochloride).
Clinical studies have shown that up to 82% of patients suffering with Parkinson's disease have difficulty swallowing and tend to dribble. Conventional selegiline tablets, syrups, and the like, still require the patient to attempt swallowing. Moreover, conventional tablets need to be administered with water, requiring another difficult swallowing act for such patients.
From a clinical perspective, it would be highly desirable to administer MAO-B inhibitors while enhancing the bioavailability of the active ingredient and avoiding first pass effect and its undesirable metabolites, hence affording a comparatively rapid onset and prolonged duration of effect as compared to conventional administration forms. Even more desirable would be the ability to administer MAO-B in a dosage form that does not present difficulty in ingestion in those patients that have difficulty swallowing, can be handled easily, and affords assurance and greater predictability of its administration and effect.